Aqueous Coating with Aqueous Coating with ShinShin--Etsu AQOATEtsu AQOAT

Shin-Etsu Chemical Technical Seminar at the Seoul National University

November 17,18 2003

Current Technique in Current Technique in Aqueous Coating with ShinAqueous Coating with Shin--Etsu Etsu

AQOATAQOAT

Basics in current aqueous formulation (one component system)

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ContentsContents

General informationCurrent aqueous formulation (one component system)An improved formulation using dual feed nozzle (two component system)

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History of Shin-Etsu AQOATHistory of ShinHistory of Shin--Etsu AQOATEtsu AQOAT

1977 Initiated research for a new enteric coating material. 1983 Developed HPMCAS. 1985 Approval of HPMCAS in Japan.1988 Submitted Drug Master File to FDA (14272).

Listed on “Japanese Pharmaceutical Excipients.”2000 FDA inspected.2001 FDA approved. Applied for the USP.2003 Draft appeared in USP Forum.

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Current commercial situation Current commercial situation (HPMCAS)(HPMCAS)Countries (production cite):

Japan, Korea, USA, Belgium, GermanyCommercial products appear in most of the European

countries.

Active ingredients: Antibiotics, Digestive enzymes, Anti-depressant, Anti-hypertensive, Hormones, Vitamins, Anti-inflammatory etc.

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Chemical Structure of HPMCASChemical Structure of HPMCAS

O

O

OO

CH2OR

CH2OROR

OR OR

OR n

R = -H -CH3-CH2CH(CH3)OH-COCH3-COCH2CH2COOH

General Name: Hydroxypropyl Methylcellulose Acetate SuccinateIUPAC Name: Cellulose, 2-hydroxypropyl methyl ether, acetate

butanedioateCAS registry number 71138-97-1

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Grades of HPMCASGrades of HPMCAS

Grade MeO HPO Acetyl SuccinoylAS-L 20.0-24.0 5.0-9.0 5.0-9.0 14.0-18.0AS-M 21.0-25.0 5.0-9.0 7.0-11.0 10.0-14.0AS-H 22.0-26.0 6.0-10.0 10.0-14.0 4.0-8.0

Substituents in wt%

AS-LG, MG, HG: Granular For organic solventsAS-LF, MF, HF: Fine powder (app. 5 mµ)For aqueous

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Various coating methods using HPMCASVarious coating methods using HPMCAS

Coating Method Additives Advantages ProcessingTime (min)*

Required coatinglevel (%-polymer)*

Organic solution None Simple 135 7

Aqueous dispersion Current method TEC, Talc, SLS Safe 138 7

Dual feed method TEC, Talc, SLS Safe, fast 90 7 - 9

Aqueous solution Ammonia Easy 197 9

Dry coating TEC, Myvacet, Talc No water 128 9

* Lab-scale tablet coating test for 8mm tablet

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Aqueous Coating SystemAqueous Coating System

HPMCASTECTalcSLSWater

Pump

HPMCASTalcSLSWater

Pump

Pump

Plasticizer

Current methodPolymer conc. at 7%

Dual feed methodPolymer conc. up to 15%

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Dry CoatingDry Coating

Pump

TECMyvacet

HPMCASTalc

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Film Formation Process in AqueousFilm Formation Process in Aqueous

AQOAT

Drying

Close-packed structure

Continuous film formation

Fused

Sprayed Water

For both current and dual feed methods

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Basic Formulation of Current Coating Basic Formulation of Current Coating Suspension Suspension

Current formulation :

AS-MFTEC *SLS **Talc WaterTotal

* Triethyl citrate, ** Sodium lauryl sulfate ( Sodium dodecyl sulfate ).

7.0 % Enteric polymer1.96 ( 28 % ) Plasticizer0.21 ( 3% ) Wetting agent2.1 ( 30% ) Anti sticking agent

88.73100.0 %

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Preparation of Coating Suspension Preparation of Coating Suspension

Talc AQOAT TEC SLS Water below 25˚C

Dissolving

Dispersing

Coating suspension

Keep below 25˚C with gentle stirring.

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Dissolution of TEC

Dispersion of AQOAT powder

Coating suspension

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Minimum Film Formation Temperature Minimum Film Formation Temperature (MFT) of AQOAT AS(MFT) of AQOAT AS--MF TypeMF Type

MFT

(˚C

)

4030201000

1020304050607080

TEC (%)

AS-MFStandard plasticizer levelfor AS-MF type

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Heat SensitivityHeat SensitivityCoagulation Temp. vs. Conc. of SuspensionCoagulation Temp. vs. Conc. of Suspension

1210864200

10

20

30

40

Concentration (%)

Coa

gula

tion

tem

pera

ture

(˚C

)

AQOAT

AQOAT + SLS 3%

Current formulation

Old formulation

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Heat SensitivityHeat SensitivityCoagulation Temp. vs. Amount of TECCoagulation Temp. vs. Amount of TEC

Current formulation

4030201000

10

20

30

40

Amount of TEC (%)

7% conc. SLS 3%

10% conc.

Coa

gula

tion

tem

pera

ture

(˚C

)

Old formulation

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Summary of Heat SensitivitySummary of Heat Sensitivity

Old Current

Polymer conc. 10 % 7 %Wetting agent None SLS 3%Coagulation temp. 20˚C 28˚CGun blockage temp. 30˚C 38˚C

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Heating Tendency of Commercial Coating Heating Tendency of Commercial Coating MachinesMachines

Exhaust air

Drying air

Mouse ringfrom front door

Water

Drying air

Exhaust air

Normal flow (parallel)

Water

Exhaust air

Drying air

Reverse flow

Water

Exhaust air

Drying airInner duct

Water

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Heating Tendency of Commercial Coating Heating Tendency of Commercial Coating MachinesMachines

* Drying airflow system; A: normal flow, B: reverse flow, C: mouse ring (from front door), D: inner duct.Note: in every cases water temperature for spraying at 20˚C. Spray rate is indicated as that per one gun.

Coating machine Charge (kg)

System* Numberof gun

Spray rate

(g/min)

Temperature of sprayed water (˚C)80˚C 70˚C

HI-COATERHCT-MINIHCT-48N

HCT-100N

0.3556060

CCACA

11122

225253535

3938353026

3534332825

AQUACOATERAQC-48TAQC-100

560

DD

12

2535

2925

2824

DRIACOATERDRC-200

DRC-500

DRC-1200

0.30.355

100

ABAAA

11213

33132560

4936362830

4433332728

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Tablet Coating 1Tablet Coating 1

Machine New Hi-Coater HCT-48NCharge 5 kg (placebo: 8 mm, 200 mg)Spray gun Schlick type Nozzle 1.8 mmSpray air 150 L/min, 200 kPaGun position 16 cm from tablet bed surfaceCoating quantity 8 % based on AQOATSuspension temp. 20~25˚CPost drying Supply air temp. 60˚C, 30 min

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Tablet Coating 2Tablet Coating 2

Step 1 st 2 nd

Supply air flow 2.4 m3/min 3.0 m3/minSupply air temp. 70˚C 80˚CExhaust air temp. 47˚C 48˚CTablet temp. 45˚C 47˚CSpray feed 25 g/min 45 g/minPan revolution 16 rpm 20 rpmLiquid consumption 714 g 5000 gSpray time 29 min 111 min

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Acid Resistance 1Acid Resistance 1

109876540

10

20

30

40Current formulationAS-MF 7% conc. SLS 3%AS-MF 10% conc.Old formulation

Coating (%)

Num

ber

of c

hang

ed

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Acid Resistance 2Acid Resistance 2

109876540

2

4

6

8

Coating (%)

Wei

ght i

ncre

asin

g (%

)

Current formulationAS-MF 7% conc. SLS 3%AS-MF 10% conc.Old formulation

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Current Aqueous Formulation Current Aqueous Formulation (One Component System)(One Component System)

Faster spray feeding (almost no viscosity)[optimum spray feed rate is doubled]Room temperature handlingGood film formation

Wet condition should be suitable for Shin-Etsu AQOAT.

Latest Development in Latest Development in Aqueous Coating with ShinAqueous Coating with Shin--Etsu Etsu

AQOATAQOAT

An improved formulation using dual feed nozzle (two component system)

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ProblemProblem……..

The current formulation still has some heat-sensitivityLower polymer concentration

One solution is “Dry Coating”The other one is ….

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Concept of Two Component SystemConcept of Two Component System

Heat sensitivity derive from the presence of plasticizer in the polymer dispersion

Polymer dispersion without plasticizer shows almost no coagulation tendencySeparation, but spraying with same spray nozzle to prevent dusting and to achieve good film formation

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Dual Feed Concentric NozzleDual Feed Concentric Nozzle

3 mm

Concentric dual-feed nozzle

Inner for polymer suspensionOuter for plasticizer

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Atomizing ConditionsAtomizing Conditions

Two component system has dusting tendency (polymer dispersion without plasticizer easily recover original powder)Atomizing conditions should be wet as much as possible

: Close gun position: High spray feed rate: Special device design (left

photo): Low atomizing air flow ratespiral straight

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Formulation for Separation SystemFormulation for Separation System

Polymer dispersionAQOAT (AS-MF) 15.0 partsTalc 4.5Sodium lauryl sulfate 0.15Water 80.35PlasticizerTriethyl citrate (TEC) 100 parts

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Tablet Coating 3Tablet Coating 3

Machine New Hi-Coater HCT-100NCharge 60 kg (placebo: 8 mm, 200 mg)Spray gun Dual feed nozzle 1.8 mm x 2Spray air 120 L/min, 400 kPaGun position 10 cm from tablet bed surface

(20 cm for current, 25 cm for Pharmacoat)Coating quantity 8 % based on AQOATSuspension temp. 20~25˚CPost drying Supply air temp. 60˚C, 30 min

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Tablet Coating 4Tablet Coating 4

Step 1 st 2 nd

Supply air flow 13 m3/min 15 m3/minSupply air temp. 70˚C 75˚CExhaust air temp. 44˚C 35˚C

(41˚C) (40˚C)Spray feed 100 g/min 250 g/min

(110 g/min) (220 g/min)Spray feed for plasticizer 4.3 g/min 10.8 g/minPan revolution 5 rpm 10 rpmSpray time 80 min [2%] 93 min [6%]*

* Expressed as polymer consumption( ) indicate conditions for current formulation

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Pilot TestPilot TestPolymer pump

Plasticizer pump

Hi-CoaterHCF-100NBatch size 60

kg

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Photo (Pilot Scale Test)Photo (Pilot Scale Test)

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Acid Resistance 3Acid Resistance 3

0

10

20

30

40

50

60

Tab

let d

efec

t (%

)

70

5 6 7 8 9Coating amount (% - polymer basis)

Dual-Pilot AS-MF 15%Current-Lab AS-MF 7%

Dual-Lab AS-MF 15%

Current-Pilot AS-MF 7%

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Inside of Pan after CoatingInside of Pan after Coating

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ResultsResults

Successfully achievedSlightly lower gastric resistance due to high polymer concentration (15%).

No nozzle-blocking

Reduced coating time (approx. half)

Clean inside of pan after coating